PCT Patent Application Publication Number WO 93/07128 ("Jadhav et al.") discloses that N,N'-disubstituted cyclic urea compounds are selective inhibitors of human immunodeficiency virus (HIV) protease, and as such, may be useful in the treatment of acquired immunodeficiency syndrome (AIDS). Jadhav, et al. teach that N,N'-symmetrically disubstituted cyclic urea compounds can be synthesized by reacting an unsubstituted cyclic urea compound with excess strong base and excess alkylating agent. Jadhav, et al. also teach that N,N'-non-symmetrically disubstituted cyclic urea compounds can be synthesized by reacting an unsubstituted cyclic urea compound with less than two equivalents of alkylating agent followed by chromatographic separation of the resulting mixture comprising unsubstituted cyclic urea compound, monosubstituted cyclic urea compound, and symmetrically disubstituted cyclic urea compound, followed by treating the isolated monosubstituted cyclic urea compound with strong base and an alkylating agent.
The present invention provides an improved method for the preparation of N,N'-disubstituted cyclic urea compounds, and is particularly advantageous for the preparation of N,N'-non-symmetrically disubstituted cyclic urea compounds, and precursors and derivatives thereof.